Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Secondary fracture prevention in primary care: a narrative review.

The global burden of osteoporosis continues to rise with an ageing population. Untreated osteoporotic fractures not only heighten the risk of subsequent fractures but are associated with excess mortality. Although primary care guidelines consistently stress the importance of secondary fracture prevention, fewer than 20% of patients are appropriately treated for osteoporosis following an initial osteoporotic fracture. This worldwide phenomenon is known as the osteoporosis care gap. This literature review examines the barriers to secondary fracture prevention in primary care and evaluates the effectiveness of targeted primary care interventions. Common themes emerged from the majority of qualitative studies, including a need for improved communication between the hospital team and primary care, better defined responsibilities and osteoporosis-directed education for the primary care physicians. Quantitative studies demonstrated that most targeted, intensive interventions aimed at educating patients and their primary care physician about osteoporosis treatment significantly increased rates of investigation and treatment. Greater uptake of models of secondary fracture prevention in primary care is urgently needed to address the osteoporosis care gap.

Expanding access to fracture liaison services in Australia for people with minimal trauma fractures: a system dynamics modelling study.

OBJECTIVES: To project how many minimal trauma fractures could be averted in Australia by expanding the number and changing the operational characteristics of fracture liaison services (FLS). STUDY DESIGN: System dynamics modelling. SETTING, PARTICIPANTS: People aged 50 years or more who present to hospitals with minimal trauma fractures, Australia, 2020-31. MAIN OUTCOME MEASURES: Numbers of all minimal trauma fractures and of hip fractures averted by increasing the FLS number (from 29 to 58 or 100), patient screening rate (from 30% to 60%), and capacity for accepting new patients (from 40 to 80 per service per month), and reducing the proportion of eligible patients who do not attend FLS (from 30% to 15%); cost per fracture averted. RESULTS: Our model projected a total of 2 441 320 minimal trauma fractures (258 680 hip fractures; 2 182 640 non-hip fractures) in people aged 50 years or older during 2020-31, including 1 211 646 second or later fractures. Increasing the FLS number to 100 averted a projected 5405 fractures (0.22%; $39 510 per fracture averted); doubling FLS capacity averted a projected 3674 fractures (0.15%; $35 835 per fracture averted). Our model projected that neither doubling the screening rate nor reducing by half the proportion of eligible patients who did not attend FLS alone would reduce the number of fractures. Increasing the FLS number to 100, the screening rate to 60%, and capacity to 80 new patients per service per month would together avert a projected 13 672 fractures (0.56%) at a cost of $42 828 per fracture averted. CONCLUSION: Our modelling indicates that increasing the number of hospital-based FLS and changing key operational characteristics would achieve only moderate reductions in the number of minimal trauma fractures among people aged 50 years or more, and the cost would be relatively high. Alternatives to specialist-led, hospital-based FLS should be explored.

Deletion of the chondrocyte glucocorticoid receptor attenuates cartilage degradation through suppression of early synovial activation in murine posttraumatic osteoarthritis.

OBJECTIVE: Disruption of endogenous glucocorticoid signalling in bone cells attenuates osteoarthritis (OA) in aged mice, however, the role of endogenous glucocorticoids in chondrocytes is unknown. Here, we investigated whether deletion of the glucocorticoid receptor, specifically in chondrocytes, also alters OA progression. DESIGN: Knee OA was induced by surgical destabilisation of the medial meniscus (DMM) in male 22-week-old tamoxifen-inducible glucocorticoid receptor knockout (chGRKO) mice and their wild-type (WT) littermates (n = 7-9/group). Mice were harvested 2, 4, 8 and 16 weeks after surgery to examine the spatiotemporal changes in molecular, cellular, and histological characteristics. RESULTS: At all time points following DMM, cartilage damage was significantly attenuated in chGRKO compared to WT mice. Two weeks after DMM, WT mice exhibited increased chondrocyte and synoviocyte hypoxia inducible factor (HIF)-2α expression resulting in extensive synovial activation characterised by synovial thickening and increased interleukin-1 beta expression. At 2 and 4 weeks after DMM, WT mice displayed pronounced chondrocyte senescence and elevated catabolic signalling (reduced Yes-associated protein 1 (YAP1) and increased matrix metalloprotease [MMP]-13 expression). Contrastingly, at 2 weeks after DMM, HIF-2α expression and synovial activation were much less pronounced in chGRKO than in WT mice. Furthermore, chondrocyte YAP1 and MMP-13 expression, as well as chondrocyte senescence were similar in chGRKO-DMM mice and sham-operated controls. CONCLUSION: Endogenous glucocorticoid signalling in chondrocytes promotes synovial activation, chondrocyte senescence and cartilage degradation by upregulation of catabolic signalling through HIF-2α in murine posttraumatic OA. These findings indicate that inhibition of glucocorticoid signalling early after injury may present a promising way to slow osteoarthritic cartilage degeneration.

Association of dietary fiber and risk of hip fracture in men from the Framingham Osteoporosis Study and the Concord Health and Ageing in Men Project.

BACKGROUND: Data in the Offspring Framingham Osteoporosis Study (FOS) suggested that higher intake of dietary fiber was modestly protective against loss of bone mineral density at the femoral neck in men but not in women. AIM: To examine the relationship of fiber intake with risk of hip fractures in men. METHODS: We included 367 men from the FOS Original cohort, 1730 men from the FOS Offspring cohort, and 782 men from the Concord Health and Ageing in Men Project (CHAMP) in the analysis. Incident fractures were defined as medically confirmed first occurrence of osteoporotic fractures at the proximal femur. Fiber intake was estimated via a validated food frequency questionnaire (FFQ) or diet history. Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A random-effects model was used to estimate the pooled relative risk in meta-analysis. RESULTS: Seventy-two incident hip fractures were identified, of which 24 occurred in the FOS Original cohort [mean (SD): age 75.3 (5.1) years; follow-up time: 8.5 (6.2) years; dietary fiber: 19 (8) (g/d)], 19 in the FOS Offspring cohort [58.8 (9.8) years; 11.0 (5.9) years; 19 (8) (g/d)], and 29 in CHAMP [81.4 (4.5) years; 5.2 (1.5) years; 28 (10) (g/d)]. We did not find significant associations within each cohort between fiber intake and risk of hip fractures. The pooled HR (95% CI) was 0.80 (0.39, 1.66) comparing energy-adjusted dietary fiber at tertile 3 vs. tertile 1 (I2 = 0, p = 0.56). CONCLUSION: These data suggested that dietary fiber was not associated with risk of incident hip fractures in men.

Appetite, oral health and weight loss in community-dwelling older men: an observational study from the Concord Health and Ageing in Men Project (CHAMP).

BACKGROUND: Unintended weight loss and the reduction in appetite are common phenomenon among older people. Reduced appetite has been linked to medication related reductions in saliva production, reduced taste ability and poor oral health. Poor appetite can result in reduced nutrient intake ensuing weight loss. It is possible that poor appetite is a mediating step on the causal pathway between oral health and weight loss. This study investigates whether poor oral health and loss of appetite are related to weight loss. METHODS: This is an observational study where data were obtained from the Concord Health and Ageing in Men Project (CHAMP). Information on socio-demographics, appetite and health related behavior was collected by self-completed questionnaire. Intraoral assessment was conducted by calibrated oral health therapists. Height and weight were measured by trained staff. Regression analysis investigated associations between oral health and appetite as risk factors for weight loss. RESULTS: Participants included 542 community dwelling older males. 99 older men (18.3%) experienced 5% or more weight loss over 3 years. Men who lost weight from baseline had lower BMI and lower body weight, had higher prevalence of frailty and depression, reported poorer appetite, and had fewer teeth (13.8 ± 9.5) than those who did not lose weight (16.3 ± 9.3). Before adjustment, the prevalence ratio (PR) for weight loss was 1.76 (95% Confidence Interval (CI), 1.19-2.59) for participants with 0-19 natural teeth present compared to those with 20 or more teeth. When adding appetite and other variables to the model, the PR for number of teeth and weight loss was unchanged: 1.78 (95% CI, 1.06-3.00). The mediation analysis showed that the indirect effect of appetite on the association between number of natural teeth on weight loss was not found to be significant. CONCLUSION: This study found that number of natural teeth present and appetite are independently related to weight change among elderly men in Australia. Tooth loss can increase the risk of swallowing difficulty leading to change in food preference, avoidance of foods and a decrease in energy intake. Our study showed the importance of oral health interventions to encourage maintenance of 20 or more natural teeth in older people.

Proinflammatory Diet Increases Circulating Inflammatory Biomarkers and Falls Risk in Community-Dwelling Older Men.

BACKGROUND: The relations between diet, chronic inflammation, and musculoskeletal health are unclear, especially among older men. OBJECTIVE: This study aimed to determine associations of the Dietary Inflammatory Index (DII) with inflammatory biomarkers, musculoskeletal health, and falls risk in community-dwelling older men. METHODS: The cross-sectional analysis included 794 community-dwelling men, mean age 81.1 ± 4.5 y, who participated in the 5-y follow-up of the Concord Health and Aging in Men Project. Of these, 616 were seen again 3 y later for the longitudinal analysis. Energy-adjusted DII (E-DII) was calculated from a validated diet history questionnaire. Bone mineral density (BMD) was measured using DXA. Twenty-four inflammatory biomarkers were analyzed. Incident falls over 3 y were determined through telephone interviews every 4 mo. Multiple regression, linear mixed effects models, negative binomial regression, and mediation analysis were utilized in this study. RESULTS: A higher E-DII score (indicating a more proinflammatory diet) was associated with higher concentrations of IL-6 (ß: 0.028 pg/mL; 95% CI: 0.003, 0.053), IL-7 (ß: 0.020 pg/mL; 95% CI: 0.002, 0.037), and TNF-α (ß: 0.027 pg/mL; 95% CI: 0.003, 0.051). A higher E-DII score was also associated with lower appendicular lean mass adjusted for BMI (ALMBMI) (ß: -0.006 kg/m2; 95% CI: -0.010, -0.001). For every unit increase in E-DII (range: -4.91 to +3.66 units), incident falls rates increased by 13% (incidence rate ratio: 1.13; 95% CI: 1.05, 1.21) over 3 y. Mediation analysis showed that the association between E-DII and 3-y incident falls was influenced by the concentrations of IL-7 by 24%. There was no association between E-DII and BMD. CONCLUSIONS: Consumption of a proinflammatory diet was associated with increased concentrations of IL-6, IL-7, and TNF-α; increased falls risk; and lower ALMBMI in community-dwelling older men. The association between incident falls and E-DII was partly mediated by concentrations of IL-7.

Contribution of psychosocial factors to socioeconomic inequalities in mortality among older Australian men: a population-based cohort study.

BACKGROUND: Among older people, the extent to which psychosocial factors explain socioeconomic inequalities in mortality is debated. We aimed to investigate the potential mediating effect of psychosocial factors on socioeconomic inequalities in mortality. METHODS: We used data from a prospective population-based cohort (the Concord Health and Ageing in Men Project; baseline recruitment in 2005-2007), in Sydney, Australia. The main outcomes were all-cause and cause-specific mortality. Socioeconomic status (SES; educational attainment, occupational position, source of income, housing tenure, and a cumulative SES score) was assessed at baseline. Measures of structural and functional social support, as well as depressive and anxiety symptoms were assessed three times during follow-ups. Associations were quantified using Cox regression. Mediation was calculated using "change-in-estimate method". RESULTS: 1522 men (mean age at baseline: 77·4 ± 5·5 years) were included in the analyses with a mean (SD) follow-up time of 9·0 (3·6) years for all-cause and 8·0 (2·8) years for cause-specific mortality. At baseline, psychosocial measures displayed marked social patterning. Being unmarried, living alone, low social interactions, and elevated depressive symptoms were associated with higher risk of all-cause and cardiovascular disease (CVD) mortality. Psychosocial factors explained 35% of SES inequalities in all-cause mortality, 29% in CVD mortality, 12% in cancer mortality, and 39% in non-CVD, non-cancer mortality. CONCLUSION: Psychosocial factors may account for up to one-third of SES inequalities in deaths from all and specific causes (except cancer mortality). Our findings suggest that interventional studies targeting social relationships and/or psychological distress in older men aiming to reduce socioeconomic inequalities in mortality are warranted.

Socioeconomic status, health-related behaviours, and death among older people: the Concord health and aging in men project prospective cohort study.

BACKGROUND: Conflicting evidence exists regarding the association of socioeconomic status (SES) with mortality among older people and little is known about the mechanisms underlying this association. We investigated the association of SES with mortality among older Australian men. We also investigated potential mediating effects of health-related behaviours in SES-mortality associations. METHODS: We used data from a prospective population-based cohort (the Concord Health and Aging in Men Project), in Sydney, Australia. The main outcomes were all-cause and cause-specific mortality. Educational attainment, occupational position, source of income, housing tenure, and a cumulative SES score were assessed at baseline. Longitudinally assessed alcohol consumption, smoking, physical activity, and body mass index were investigated as potential mediators. Associations were quantified using Cox regression. RESULTS: We evaluated 1527 men (mean age: 77.4 ± 5.5 years). During a mean follow-up time of 9.0 years, 783 deaths occurred. For deaths from all causes, the adjusted hazard ratio (HR) for the lowest tertile of cumulative SES score versus the highest tertile was 1.44 (95% CI 1.21 to 1.70); the corresponding sub-HRs were 1.35 (0.96 to 1.89) for cardiovascular disease (CVD) mortality; 1.58 (1.15 to 2.18) for cancer mortality, and 1.86 (1.36 to 2.56) for non-CVD, non-cancer mortality. SES-mortality associations were attenuated by 11-25% after adjustment for mediating health-related behaviours. CONCLUSION: Low SES is associated with increased mortality in older Australian men and health-related behaviours accounted for less than one-fourth of these associations. Further research is needed to fully understand the mechanisms underlying SES inequalities in mortality among older people.

Osteoporosis management in Australian general practice: an analysis of current osteoporosis treatment patterns and gaps in practice.

BACKGROUND: Among Australians aged 50 and over, an estimated 1 in 4 men and 2 in 5 women will experience a minimal trauma fracture during their remaining lifetime. Effective fracture prevention is hindered by substantial undertreatment, even of patients who clearly warrant pharmacological therapy. Poor adherence to osteoporosis treatment is also a leading cause of repeat fractures and hospitalisation. The aim of this study was to identify current osteoporosis treatment patterns and gaps in practice in Australia, using general practice data, and to explore general practitioners' (GPs') attitudes to osteoporosis treatment and their views on patient factors affecting osteoporosis management. METHODS: The study was conducted in two phases. Phase 1 was a longitudinal retrospective cohort study which utilised data from MedicineInsight - a national general practice data program that extracts longitudinal, de-identified patient data from clinical information systems (CISs) of participating general practices. Phase 2 included semi-structured, in-depth telephone interviews with a sample of MedicineInsight practice GPs. Data were analysed using an inductive thematic analysis method informed by the theory of planned behaviour. RESULTS: A diagnosis of osteoporosis was recorded in 12.4% of patients over the age of 50 years seen in general practice. Of those diagnosed with osteoporosis, almost a quarter were not prescribed osteoporosis medicines. From 2012 to 17, there was a progressive increase in the number of denosumab prescriptions, while prescriptions for bisphosphonates and other osteoporosis medicines decreased. More than 80% of patients who ceased denosumab treatment had no subsequent bisphosphonate prescription recorded. Interviews with GPs revealed beliefs and attitudes that may have influenced their intentions towards prescribing and osteoporosis management. CONCLUSIONS: This study suggests that within the Australian general practice setting, osteoporosis is underdiagnosed and undertreated. In addition, it appears that most patients who ceased denosumab treatment had no record of subsequent antiresorptive therapy, which would place them at risk of further fractures. The study supports the need for the development of clinical education programs addressing GP knowledge gaps and attitudes, and the implementation of specific interventions such as good reminder/recall systems to avoid delays in reviewing and treating patients with osteoporosis.

Oral health and cognitive status in the Concord Health and Ageing in Men Project: A cross-sectional study in community-dwelling older Australian men.

BACKGROUND: Several studies have examined the relationship between cognition and oral health in older populations. To further understand this relationship, we examined the associations between cognitive function, chewing capacity and the number of teeth present in community-dwelling older males in Australia. METHODS: Data were obtained from cross-sectional analysis of fourth wave of the Concord Health and Ageing in Men Project (CHAMP). Participants were 369 community-dwelling males aged 78 years or over. Cognitive function was measured utilising the Mini-Mental State Examination (MMSE). Chewing capacity was determined on ability to chew food items of different textures, and oral health data were collected. Ordinal regression was used to analyse associations between MMSE (four categories) and chewing capacity and number of natural teeth present. RESULTS: Overall, 67.5% of participants reported that they could chew all 11 listed food items. Participants with fewer than 20 teeth were statistically significantly more likely to have cognitive impairment (unadjusted odds ratio (OR) 1.87; 95% confidence interval (CI) 1.25-2.79, adjusted OR 1.62; 95% CI 1.07-2.43). Participants with limited chewing capacity were also more likely to have cognitive impairment (unadjusted OR 1.91; 95% CI 1.25-2.94, adjusted OR 1.61; 95% CI 1.03-2.49). CONCLUSIONS: This study suggests either that older men with fewer than 20 natural teeth and those with limited chewing capacity are more likely to have an associated cognitive impairment or that those with cognitive impairment are more likely to have fewer teeth and limited chewing capacity. Further longitudinal studies should clarify these relationships.

Androgens sensitise mice to glucocorticoid-induced insulin resistance and fat accumulation.

AIMS/HYPOTHESIS: Chronic glucocorticoid therapy causes insulin resistance, dyslipidaemia, abnormal fat accumulation, loss of muscle mass and osteoporosis. Here we describe a hitherto unknown sexual dimorphism in the metabolic response to chronic glucocorticoid exposure in mice. This led us to investigate whether glucocorticoid-induced insulin resistance and obesity were dependent on sex hormones. METHODS: Male and female CD1 mice were treated for 4 weeks with supraphysiological doses (~250 µg/day) of corticosterone, the main glucocorticoid in rodents, or equivalent volume of vehicle (drinking water without corticosterone). To investigate the effects of sex hormones, a separate group of mice were either orchidectomised or ovariectomised prior to corticosterone treatment, with or without dihydrotestosterone replacement. Body composition was determined before and after corticosterone treatment, and insulin tolerance was assessed after 7 and 28 days of treatment. Adipocyte morphology was assessed in white and brown adipose tissues by immunohistochemistry, and fasting serum concentrations of NEFA, triacylglycerols, total cholesterol and free glycerol were measured using colorimetric assays. Obesity- and diabetes-related hormones were measured using multiplex assays, and RNA and protein expression in adipose tissues were measured by RT-PCR and immunoblotting, respectively. RESULTS: Chronic corticosterone treatment led to insulin resistance, fasting hyperinsulinaemia, increased adiposity and dyslipidaemia in male, but not female mice. In males, orchidectomy improved baseline insulin sensitivity and attenuated corticosterone-induced insulin resistance, but did not prevent fat accumulation. In androgen-deficient mice (orchidectomised males, and intact and ovariectomised females) treated with dihydrotestosterone, corticosterone treatment led to insulin resistance and dyslipidaemia. In brown adipose tissue, androgens were required for corticosterone-induced intracellular lipid accumulation ('whitening'), and dihydrotestosterone specifically exacerbated corticosterone-induced accumulation of white adipose tissue by increasing adipocyte hypertrophy. Androgens also suppressed circulating adiponectin concentrations, but corticosterone-induced insulin resistance did not involve additional suppression of adiponectin levels. In white adipose tissue, androgens were required for induction of the glucocorticoid target gene Gilz (also known as Tsc22d3) by corticosterone. CONCLUSIONS/INTERPRETATION: In mice, androgens potentiate the development of insulin resistance, fat accumulation and brown adipose tissue whitening following chronic glucocorticoid treatment.

Identification of Patients with Osteoporotic Vertebral Fractures via Simple Text Search of Routine Radiology Reports.

Secondary fracture prevention programs mostly identify patients with symptomatic non-vertebral fractures, whereas asymptomatic vertebral fractures are usually missed. We here describe the development and validation of a simple method to systematically identify patients with radiographic vertebral fractures using simple text-based searching of free-text radiology reports. The study consisted of two phases. In the development phase (DP), twelve search terms were used to identify vertebral fractures in all X-ray and CT reports issued over a period of 6 months. Positive reports were manually reviewed to confirm whether or not a vertebral fracture had in fact been reported. The three search terms most effective in detecting vertebral fractures during the DP were then applied during the implementation phase (IP) over several weeks to test their ability to identify patients with vertebral fractures. The search terms 'Loss of Height' (LoH), 'Compression Fracture' (CoF) and 'Crush Fracture' (CrF) identified the highest number of imaging reports with a confirmed vertebral fracture. These three search terms identified 581 of 689 (84%) of all true vertebral fractures with a positive predictive value of 76%. Using these three terms in the IP, 126 reports were identified of which 100 (79%) had a vertebral fracture confirmed on manual review. Amongst a sample of 587 reports in week 1 of the IP, 7 (1.2%) were false negatives. Many patients with vertebral fractures can be identified via a simple text-based search of electronic radiology reports. This method may be utilised by secondary fracture prevention programs to narrow the 'care gap' in osteoporosis management.

Endogenous glucocorticoid signaling in chondrocytes attenuates joint inflammation and damage.

Previous studies demonstrated that endogenous glucocorticoid signaling in osteoblasts promotes inflammation in murine immune arthritis. The current study determined whether disruption of endogenous glucocorticoid signaling in chondrocytes also modulates the course and severity of arthritis. Tamoxifen-inducible chondrocyte-targeted glucocorticoid receptor-knockout (chGRKO) mice were generated by breeding GRflox/flox mice with tamoxifen-inducible collagen 2a1 Cre (Col2a1-CreERT2) mice. Antigen-induced arthritis (AIA) and K/BxN serum transfer-induced arthritis (STIA) were induced in both chGRKO mice and their Cre-negative GRflox/flox littermates [wild type (WT)]. Arthritis was assessed by measurement of joint swelling and histology of joints collected at d 14. Neutrophil activity and gene expression patterns associated with cartilage damage were also evaluated. In both arthritis models clinical (joint swelling) and histologic indices of inflammatory activity were significantly greater in chGRKO than in WT mice. The STIA model was characterized by early up-regulation of CXCR2/CXCR2 ligand gene expression in ankle tissues, and significant and selective expansion of splenic CXCR2+ neutrophils in chGRKO arthritic compared to WT arthritic mice. At later stages, gene expression of enzymes involved in cartilage degradation was up-regulated in chGRKO but not WT arthritic mice. Therefore, we summarize that chondrocytes actively mitigate local joint inflammation, cartilage degradation and systemic neutrophil activity via a glucocorticoid-dependent pathway.-Tu, J., Stoner, S., Fromm, P. D., Wang, T., Chen, D., Tuckermann, J., Cooper, M. S., Seibel, M. J., Zhou, H. Endogenous glucocorticoid signaling in chondrocytes attenuates joint inflammation and damage.

Temporal associations between sexual function and cognitive function in community-dwelling older men: the Concord Health and Ageing in Men Project.

Background: previous cross-sectional studies have reported bidirectional associations between sexual activity and cognitive function among older people. However, the temporal associations have not been studied. Methods: community-dwelling men aged 70+ from the Concord Health and Ageing in Men Project were assessed. This study was based on 986 men at baseline, 829 men at 2 year and 595 men at 5-year follow-up. Sexual function using a standardised questionnaire (erectile function, sexual activity, sexual satisfaction, sexual desire) was analysed by generalised estimating equations to examine associations between changes in sexual function and changes in mini-mental state examination (MMSE) across three time points over 5 years. Age, BMI, comorbidity, self-rated health, smoking, number of medications, country of birth, education, marital status, depression and reproductive hormones were also measured at all time points. Results: in unadjusted models, declines in erectile function (ß = -0.317) and sexual activity (ß = -0.575) over time were statistically significantly associated with a decline in MMSE over time. The associations observed in the unadjusted models remained after adjusting for a range of covariables. Declines in sexual satisfaction and sexual desire over time were not associated with changes in MMSE. Conclusions: our findings provide evidence of a longitudinal temporal relationship between sexual activity and cognitive function. Further studies are warranted to examine whether maintaining a healthy sexual life has a positive effect on cognitive function in older men.

Association between pain and the frailty phenotype in older men: longitudinal results from the Concord Health and Ageing in Men Project (CHAMP).

Objectives: to determine whether pain increases the risk of developing the frailty phenotype and whether frailty increases the risk of developing chronic or intrusive pain, using longitudinal data. Design/Setting: longitudinal data from the Concord Health and Ageing in Men Project (CHAMP), a prospective population based cohort study. Participants: a total of 1,705 men aged 70 years or older, living in an urban area of New South Wales, Australia. Measurements: data on the presence of chronic pain (daily pain for at least 3 months), intrusive pain (pain causing moderate to severe interference with activities) and the criteria for the Cardiovascular Health Study (CHS) frailty phenotype were collected in three waves, from January 2005 to October 2013. Data on age, living arrangements, education, smoking status, alcohol consumption, body mass index, comorbidities, cognitive function, depressive symptoms and history of vertebral or hip fracture were also collected and included as covariates in the analyses. Results: a total of 1,705 participants were included at baseline, of whom 1,332 provided data at the 2-year follow-up and 940 at the 5-year follow-up. Non-frail (robust and pre-frail) men who reported chronic pain were 1.60 (95% confidence interval (CI): 1.02-2.51, P = 0.039) times more likely to develop frailty at follow-up, compared to those with no pain. Intrusive pain did not significantly increase the risk of future frailty. Likewise, the frailty status was not associated with future chronic or intrusive pain in the adjusted analysis. Conclusions: the presence of chronic pain increases the risk of developing the frailty phenotype in community-dwelling older men.

Transgenic Disruption of Glucocorticoid Signaling in Osteoblasts Attenuates Joint Inflammation in Collagen Antibody-Induced Arthritis.

The role of endogenous glucocorticoids (GCs) in rheumatoid arthritis remains unclear. Herein, we examined the role of osteoblastic GC signaling in collagen antibody-induced arthritis. Intracellular GC signaling was abrogated exclusively in mature osteoblasts via transgenic (tg) expression of 11ß-hydroxysteroid dehydrogenase type 2. Arthritis was induced in 8-week-old male tg mice and their wild-type (WT) littermates. Paw swelling was scored daily from induction to end point (day 14). Inflammation, cartilage degradation, and local bone erosion were assessed at the wrist, knee, and ankle joints. Systemic skeletal changes were determined by microcomputed tomography and histomorphometrical analysis of the tibiae. Both tg and WT mice developed acute arthritis in response to the administration of collagen antibodies. However, compared with WT mice, both clinical and histological indexes of joint inflammation were significantly mitigated in animals with disrupted osteoblastic GC signaling. In WT mice, arthritis was associated with increased bone resorption, decreased bone formation, and significant bone loss. In contrast, bone turnover and bone mass remained unchanged in tg arthritic mice. Disruption of GC signaling in osteoblasts significantly reduces joint inflammation and prevents structural bone and cartilage damage in collagen antibody-induced arthritis. These data corroborate the concept that osteoblasts modulate the inflammatory response in immune-mediated arthritis via a GC-dependent pathway.

Polypharmacy in older adults: Association Rule and Frequent-Set Analysis to evaluate concomitant medication use.

The aim of this study was to apply Association Rule and Frequent-Set analysis, and novel means of data visualisation to ascertain patterns of medication use and medication combinations contributing to medication group clusters according to geriatric syndrome status in older adults. Participants were community-dwelling men (aged ≥70 years, n=1686), Sydney, Australia. Medication exposure was categorised at medication class level and data were analysed according to geriatric syndrome status (presence of at least one syndrome including frailty, falls, cognitive impairment and urinary incontinence). Association Rule and Frequent-Set analysis were performed to identify "interesting" patterns of medication combinations that occur together. This analysis involves advanced computer algorithms that investigated all possible combinations of medications in the dataset in order to identify those which are observed more or much less frequently than expected. Frequent-Set Analysis demonstrated one unexpected medication combination, antiulcer and antidiabetic medications (3.5% of participants) in the overall population (n=1687). Frequency of medication combinations was similar in participants with (n=666) and without (n=1020) geriatric syndromes. Among participants with geriatric syndromes, the most frequent combinations included antigout with lipid-lowering agents (5.7%) followed by angiotensin II and diuretics combination (22%). This novel methodology can be used to detect common medication combinations overall by data visualisation, and against specific adverse drug reactions such as geriatric syndromes. This methodology may be a valuable pharmacovigilance approach to monitor large databases for the safety of medications.

Diet quality and its implications on the cardio-metabolic, physical and general health of older men: the Concord Health and Ageing in Men Project (CHAMP).

The revised Dietary Guideline Index (DGI-2013) scores individuals' diets according to their compliance with the Australian Dietary Guideline (ADG). This cross-sectional study assesses the diet quality of 794 community-dwelling men aged 74 years and older, living in Sydney, Australia participating in the Concord Health and Ageing in Men Project; it also examines sociodemographic and lifestyle factors associated with DGI-2013 scores; it studies associations between DGI-2103 scores and the following measures: homoeostasis model assessment - insulin resistance, LDL-cholesterol, HDL-cholesterol, TAG, blood pressure, waist:hip ratio, BMI, number of co-morbidities and medications and frailty status while also accounting for the effect of ethnicity in these relationships. Median DGI-2013 score was 93·7 (54·4, 121·2); most individuals failed to meet recommendations for vegetables, dairy products and alternatives, added sugar, unsaturated fat and SFA, fluid and discretionary foods. Lower education, income, physical activity levels and smoking were associated with low scores. After adjustments for confounders, high DGI-2013 scores were associated with lower HDL-cholesterol, lower waist:hip ratios and lower probability of being frail. Proxies of good health (fewer co-morbidities and medications) were not associated with better compliance to the ADG. However, in participants with a Mediterranean background, low DGI-2013 scores were not generally associated with poorer health. Older men demonstrated poor diet quality as assessed by the DGI-2013, and the association between dietary guidelines and health measures and indices may be influenced by ethnic background.

Longitudinal associations between body composition, sarcopenic obesity and outcomes of frailty, disability, institutionalisation and mortality in community-dwelling older men: The Concord Health and Ageing in Men Project.

Background: to explore the longitudinal associations between body composition measures, sarcopenic obesity and outcomes of frailty, activities of daily living (ADL) and instrumental ADL (IADL) disability, institutionalisation and mortality. Methods: men aged ≥ 70 years (2005-07) from the Concord Health and Ageing in Men Project were assessed at baseline (n = 1,705), 2 (n = 1,366) and 5 years (n = 954). The main outcome measures were frailty (adapted Fried criteria), ADL, including personal care and mobility and IADL disability (ability to perform tasks for independent living), institutionalisation and mortality. The Foundation for the National Institutes of Health cut-points were used for low muscle mass: appendicular lean mass (ALM):Body Mass Index (BMI) ratio (ALMBMI) <0.789 and obesity was defined as >30% fat. Generalised estimating equations were used to examine the longitudinal associations between the independent variables (obesity alone, low muscle mass and sarcopenic obesity) and frailty, ADL and IADL disability. Results: in unadjusted, age adjusted and fully adjusted analysis, men with low muscle mass showed increased risk of frailty and IADL disability. In fully adjusted analysis, men with sarcopenic obesity had an increased risk of frailty (odds ratio (OR): 2.00 (95% confidence of interval (CI): 1.42, 2.82)) ADL disability (OR: 1.58 (95% CI: 1.12, 2.24)) and IADL disability (OR: 1.36 (95% CI: 1.05, 1.76)). Obesity alone was protective for institutionalisation (OR: 0.51 (95% CI: 0.31, 0.84)) but was not associated with any other outcomes. Conclusions: low muscle mass and sarcopenic obesity were associated with poor functional outcomes, independent of confounders. This would suggest that future trials on frailty and disability prevention should be designed to intervene on both muscle mass and fat mass.